Selective Interactions of <i>O</i>-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B
A set of structurally related <i>O</i>-methylated flavonoid natural products isolated from <i>Senecio roseiflorus</i> (<b>1</b>), <i>Polygonum senegalense</i> (<b>2</b> and <b>3</b>), <i>Bhaphia macrocalyx</i> (<b...
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MDPI AG
2020-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/22/5358 |
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| author | Narayan D. Chaurasiya Jacob Midiwo Pankaj Pandey Regina N. Bwire Robert J. Doerksen Ilias Muhammad Babu L. Tekwani |
| author_facet | Narayan D. Chaurasiya Jacob Midiwo Pankaj Pandey Regina N. Bwire Robert J. Doerksen Ilias Muhammad Babu L. Tekwani |
| author_sort | Narayan D. Chaurasiya |
| collection | DOAJ |
| description | A set of structurally related <i>O</i>-methylated flavonoid natural products isolated from <i>Senecio roseiflorus</i> (<b>1</b>), <i>Polygonum senegalense</i> (<b>2</b> and <b>3</b>), <i>Bhaphia macrocalyx</i> (<b>4</b>), <i>Gardenia ternifolia</i> (<b>5</b>), and <i>Psiadia punctulata</i> (<b>6</b>) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds <b>1</b>, <b>2</b>, and <b>5</b> showed selective inhibition of MAO-A, while <b>4</b> and <b>6</b> showed selective inhibition of MAO-B. Compound <b>3</b> showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds <b>1</b>–<b>3</b> and <b>5</b> with MAO-A, and compounds <b>3</b> and <b>6</b> with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by <b>1</b> and <b>3</b>, while a partially-reversible mixed-type inhibition by <b>5</b>. Similarly, enzyme inhibition-kinetics analysis with compounds <b>3</b>, <b>4</b>, and <b>6</b>, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that <b>1</b> selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the <i>O</i>-methylated flavonoids (<b>1</b> and <b>4</b>–<b>6</b>) and chalcones (<b>2</b> and <b>3</b>) to MAO-A matched closely with the trend in the experimental IC<sub>50′</sub>s. Analysis of the binding free-energies suggested better interaction of <b>4</b> and <b>6</b> with MAO-B than with MAO-A. The natural <i>O</i>-methylated flavonoid (<b>1</b>) with highly potent inhibition (IC<sub>50</sub> 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders. |
| first_indexed | 2024-03-10T14:48:03Z |
| format | Article |
| id | doaj.art-bb4a0403ab724203909aeed6b4cc15fa |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T14:48:03Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-bb4a0403ab724203909aeed6b4cc15fa2023-11-20T21:12:47ZengMDPI AGMolecules1420-30492020-11-012522535810.3390/molecules25225358Selective Interactions of <i>O</i>-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -BNarayan D. Chaurasiya0Jacob Midiwo1Pankaj Pandey2Regina N. Bwire3Robert J. Doerksen4Ilias Muhammad5Babu L. Tekwani6Department of Infectious Diseases, Division of Drug Discovery, Southern Research, Birmingham, AL 35205, USADepartment of Chemistry, University of Nairobi, Nairobi P.O. Box 30197-00100, KenyaNational Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USADepartment of pure and applied Chemistry, Masinde Muliro University of Science and Technology, Kakamega P.O. Box 190-50100, KenyaDepartment of BioMolecular Sciences, Division of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USANational Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USADepartment of Infectious Diseases, Division of Drug Discovery, Southern Research, Birmingham, AL 35205, USAA set of structurally related <i>O</i>-methylated flavonoid natural products isolated from <i>Senecio roseiflorus</i> (<b>1</b>), <i>Polygonum senegalense</i> (<b>2</b> and <b>3</b>), <i>Bhaphia macrocalyx</i> (<b>4</b>), <i>Gardenia ternifolia</i> (<b>5</b>), and <i>Psiadia punctulata</i> (<b>6</b>) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds <b>1</b>, <b>2</b>, and <b>5</b> showed selective inhibition of MAO-A, while <b>4</b> and <b>6</b> showed selective inhibition of MAO-B. Compound <b>3</b> showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds <b>1</b>–<b>3</b> and <b>5</b> with MAO-A, and compounds <b>3</b> and <b>6</b> with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by <b>1</b> and <b>3</b>, while a partially-reversible mixed-type inhibition by <b>5</b>. Similarly, enzyme inhibition-kinetics analysis with compounds <b>3</b>, <b>4</b>, and <b>6</b>, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that <b>1</b> selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the <i>O</i>-methylated flavonoids (<b>1</b> and <b>4</b>–<b>6</b>) and chalcones (<b>2</b> and <b>3</b>) to MAO-A matched closely with the trend in the experimental IC<sub>50′</sub>s. Analysis of the binding free-energies suggested better interaction of <b>4</b> and <b>6</b> with MAO-B than with MAO-A. The natural <i>O</i>-methylated flavonoid (<b>1</b>) with highly potent inhibition (IC<sub>50</sub> 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.https://www.mdpi.com/1420-3049/25/22/5358recombinant monoamine oxidase-Amonoamine oxidase-Bneurological disorderenzyme kineticsmolecular dockinginhibition activity |
| spellingShingle | Narayan D. Chaurasiya Jacob Midiwo Pankaj Pandey Regina N. Bwire Robert J. Doerksen Ilias Muhammad Babu L. Tekwani Selective Interactions of <i>O</i>-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B Molecules recombinant monoamine oxidase-A monoamine oxidase-B neurological disorder enzyme kinetics molecular docking inhibition activity |
| title | Selective Interactions of <i>O</i>-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
| title_full | Selective Interactions of <i>O</i>-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
| title_fullStr | Selective Interactions of <i>O</i>-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
| title_full_unstemmed | Selective Interactions of <i>O</i>-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
| title_short | Selective Interactions of <i>O</i>-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
| title_sort | selective interactions of i o i methylated flavonoid natural products with human monoamine oxidase a and b |
| topic | recombinant monoamine oxidase-A monoamine oxidase-B neurological disorder enzyme kinetics molecular docking inhibition activity |
| url | https://www.mdpi.com/1420-3049/25/22/5358 |
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